Substituted phenoxyalkyl ethers



rammed Aug. 24, 1943 7 Henry R. Henze, Austin, Tex; assignor to Parka' 7 Davis 8a Company, Detroit,' Mich.,-ralcorporation of Michigan I No DrawinmljApplication April 17, 1940,

- oSerial N0. 330,064 I The invention relates to a new class-,ofamethyl phenyl ethers wherein a hydrogen .zatom ofF-the methyl group of same ethers} 51s replaice'dibysa 5- -hydrocarbon-substituted hydantoin radical. More especially, the invention refers 'to menew Mass of? compounds of the following general-formula, v

where RT-is -.a hydrocarbon; rad-icali such as satu- ;rated @011 unsaturated -alkyl, ,--substituted' al-kyl, l henyl; substituted, :phenyl X .yrepre'senti-ng 12a member of the group hydrogen, an alkali metal, an calkali-neeearth metal rand z'magnesiugnmuThe newreompoundsr-may thereforealsol be designated was a5-hydrocarbon subStitutede-E-phenoxymethyl hydantoins. $1. I 1 1' f.

s'llhernew compounds of the-invention may read- =-ilysbe1aobtained-;;by: reacting an alkali eyanide.-and i ammoniumcarbonate r-w-ithnaiphenoxymethyl:(a1- ikyl ke-tone aor-,;;phenex fmeth-yl saryli ketonegor nphenoxymethyl' vzaralkyl; ketoneforzlike; phenoxyimethyl'ketone eithe formula, I;

where R has the same significance as given in the above hydantoin formula.

The following examples-will-serve to illustrate the invention.

150 grams (1 mole) of.phenokymethylrmiethyl sketonefifareziaddedrto a mixtureirofitflzfiag'rams of potassium cyainidea t-lz3izrnolesl ,ealoout; 3r molescof freshly powdered ammoniumcarbonate and 2 liters of 50% alcohoL- The mixture is immersed for 9 or 10 hours in a water bath, kept at a temperature of about -55-*60FC'.' The flask containing the mixture is equippedlwith an air condenser of an alkali metal or alkaline earth metal or magnesium compound with the 'hydantoinlf .After heating at .C., thereaetion mixture is heated 3more"hou'rs at 'about"90"C. "Thecontents of'the flask. are acidified and cooledand the precipitate filtered ofi, dissolved in'alcohol and. treated with decoloiiz'ingcharcoal (Norite) The charcoaled alcoholic solution is filtered from the Norite, diluted with water and the ii-phenoXymethyl-5-methyl hydantoin which precipitates out is filtered oli. It has a melting point of 147 C. (corrected), is very soluble in"% -alcohol and-acetone and moderately soluble in 50% alcohol and water.

Analysis: calculated for C11H12O3N2IC, 59.97;

"Found: C,-59.65; H, 5.-63;-N, 12.81. 1

The hydantoinate salts of the product oft-his example corresponding to the compoundsuof'the general formula in which X- represents analkali or alkaline earth'metal or magnesium areobtained by reacting a basic or alkaline solution EXANLPLE :2

The intermediate phenoxymethyl npropylketone used in this example is a new compound and can be prepared as follows: c

49.2 grams of'neprcpyl bromidetflze mole) are diluted with cc. of anhydrous ether and the mixture added to 1105 parts of magnesium 'turnings to form the propyl magnesium bromideCtrighard reagent. Onepart of phenoxy acetonitrile 'ais'i theniadded With-100 cc. of dry ether.

action product is, warmed gently for l hour, cooled iman ice-.Fbath and decomposed withice cold 10% hirdrochloricacid. .lIhe plienoxymethyl .n=p1 0py1 The "reketone ;is separated, dried over anhydrous-calcium chloride, thetd'ry ethereal-solution separated from the Calcium chloride, the-ether-evaporated off and the phenoxymethyl npropylktonefob ijtained asI-afractiomboiled at 1l2 C. (corrected) "i.'at.4-. mm. pressure. .lItanaly'zes. ahnostitheltheoretical percentages of carbon and hydregerrror 45411118 formula C11H1402.

178 grams (1 mole) -of phenoxymethyl n p'ropyl "ketonegprepared'for example as describdlabove, .are rhixe'd with 1.3 moles' of potassium-cyanide, 3

- moles oiammoni-um carbOnate-and I-EIOO- 01- 1600 cc. of 50% alcohol in a flask equipped with an air-condenser. The mixture is immersed for 10 hours in a water bath maintained at 60 C. At the end of this time, the mixture is heated to 90 C. and kept at this temperature for 2 or 3 hours. The contents of the flask are acidified, cooled, the precipitate filtered off, taken up in alcohol, treated with decolorizing charcoal and the clarified alcoholic solution treated with water to cause separation of -phenoxymethyl-5-n-propyl hydantoin melting at 149 C. (corrected).

The product of this example can be converted into its hydantoinate salts the same way as described above for the product of Example 1.

The examples serve to illustrate the invention but it is not limited to the details and specific compounds mentioned therein. For instance, I have similarly prepared numerous other 5-alkyland 5-aryl-5-phenoxymethyl hydantoins as well as the intermediate phenoxymethyl ketones necessary for their synthesis. Some of the intermediates and final products are as follows:

TABLE I Phenoxymethyl ketones, CsHsOCHzC'O-R R -on. 01mm -n-o.n1 nO Hp B.P. O.(corr.) -112 98 100 112 Min. of mer- I cury 12 5 4 I 4 M01. ref;

Calcd 41.82 46. 43 51.05 55.67 Found..... 42. 06 46. 47 51. 18 55. 76

Carbon, per 0 cent:

Calcd 71.96 73. 13 74; ll 74.95 Found"... 71. 80 73; 42 74. 07 75. 48

Hydrogen, per cent:

Calcd 6. 72 7. 37 7. 92 8. 30 Found-.. 7.02 7. 24 8.06 8.61

S e m i c a r b a zone, M. P. C .Q... 176 101.5 108.5 76

(COIL) 117 153 187 Mm. of mercury 4 v 1 10 8 20 Phenoxyd 1. 0283 1.0025 1. 6067 methyL 20 I Phenyl ken 1.5065 1.4960 1.5035 o n e M.-P.,74 M01. ref.: (0011.)

Calcd 55. 67 60.29 29 Found.-." 55. 56 60. 07 60. 58

Carbon, per- .1 cent: A Calcd 74. 95 75. G8 75. 68 79.21

Found 75. 05 75. 52 55 79. 06'

Hydrogen, per

cent:

Caled 8.39 8. 78 8. 78 5. 71.. Found.-." 8. 57 9. 01 8. 66 5. 74"

- Semicarbazone, 1 l

M. P., Liquid 87. 5-88 0 83. 5 84.0 187. 0 187.5

. TABLE II S-phenorymethyZ-S-alkyl or phenylhydantoin 3 2 2N2)\CH2CHz0CaH5 R CH3 -CIH5 DG3H1 IlC4H.

(com) 147 176 149 162 Carbon, per

cent:

Calcd 59.97 61.50 62.87 64.10 Found 59. 65 61. 60 62. 67 63. 74

Hydrogen, per

cent: Galcd 5.50 6.02 6.50 6.92 Found 5.03 0.05 6.63 6.89

Nitrogen, per

- cent:

Calcd 12. 73 .11. 97 11. 28 10. 68 Found- 12. 81 12. 28 11. 30 10. 30

-R -so.m -n-0.H.. -io.H.. 0.H.

M. P. C.

(comjnn-u 166 181.5 181 Carbon, per

cent:

Calcd 64.10 65.18 65.18 68.08 Found- 63. 75 65. 18 64. 92 68. 00

Hydrogen, Per 7 7 cent:

Calcd 6.92 7.30 7.30 5.00 Found..." 7. 22 7 38 7. 54 5. l3

Nitrogen, per cent: 1

Calcd 10.68 10.19 10.19 9.93 Found. 10.50 10.00 10.40 10.01

Other compounds coming within the general formula can be made from the corresponding phenoxymethyl ketones in which R of the general phenoxymethyl ketone formula is a hydrocarbon radical such as benzyl, cyclohexyl, tolyl, cinnamyl, etc. Y

The compounds are useful as intermediates for the preparation of pharmaceutically useful-compounds. Many of them aredirectly usefulfor therapeutic purposes, especially fas anticonvulsants. f

The preferred hydantoin compounds arethose.

. containing less than about 6 carbon atoms. 1

As described above under Example 1', the hydantoinate salts of alkali metals-and alkaline earth metals and magnesium are obtained by reacting abasic or alkaline solution of an alkali metal or alkaline earth metal or magnesium compound with any of the above mentioned hydantoins.

WhatIclaim is:

1. Hydantoin-substituted phenyl methyl ethers of the formula,

and their corresponding alkali metal, alkaline earth metal, and magnesium hydantoinate salts, R being a lower alkyl radical, prepared for use asatherapeutic agent. I 1

2. The sodium salt'of a hydantolmsubstituted phenyl methyl'ether of theformula 1 my 13 m -be t use as a therapeutic agent. HENRY R. I-IENZE.

where R is a lower alkyl radical, prepared for use 4. 5-phenoxymethyl-5-ethyl hydantoin, preas a. therapeutic agent. pared for use as therapeutic agent.

3. 5-phenoxymethyl-5-ethyl hydantoin, and its 5. The sodium salt of 5-phenoxymethyl-5-ethyl corresponding alkali metal, alkaline earth metal, hydantoin, prepared for use as a therapeutic and magnesium hydantoinate salts, prepared for 5 agent.

Certificate of Correction Patent No. 2,327,890. August 24, 1943.

HENRY R. HENZE It is hereby certified that error appears in the printed specification of the above numbered patent requ1rmg correctlon as follows: Page 2, second column, lines 3 and 4, Table II, for

and that the said Letters Patent should be read with this correction therein that the same may conform to the record of the case in the Patent Oflice.

Signed and sealed the 4th day of July, A. D. 1944.

[SEAL] LESLIE FRAZER,

Acting Commissioner of Patents. 

